The present invention relates to a novel process for preparing an aromatic compound substituted by a tertiary nitrile which is applicable to the preparation of a wide variety of compounds of this type. Such tertiary-nitrile-substituted aromatic compound final products comprise compounds of Formula (1.0.0): ##STR4##
wherein: the constituent parts W.sup.1, W.sup.2, W.sup.3, W.sup.4, and W.sup.5, and the substituent moieties R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 all have the meanings set out in detail further below. The process of the present invention may be illustrated by the follow reaction scheme: ##STR5## PA1 wherein R.sub.a is hydrogen, (C.sub.1 -C.sub.6) alkyl phenyl or (C.sub.1 -C.sub.3) alkyl-phenyl wherein said phenyl groups are optionally substituted by one or two --(C.sub.1 -C.sub.4) alkyl, --O(C.sub.1 -C.sub.3) alkyl, Br, or Cl; R is hydrogen, (C.sub.1 -C.sub.6) alkyl, --(CH.sub.2).sub.n (C.sub.3 -C.sub.7) cycloalkyl where n is 0 to 2, or --(Z').sub.b (C.sub.6 -C.sub.10) aryl where b is 0 or 1 and Z' is (C.sub.1 -C.sub.6) alkylene or (C.sub.2 -C.sub.6) alkenylene, where said alkyl and aryl moieties of said R groups are optionally substituted by one or more halo, preferably F or Cl, hydroxy, (C.sub.1 -C.sub.5) alkyl, (C.sub.1 -C.sub.5) alkoxy, or trifluoromethyl; and R.sup.1 is hydrogen, (C.sub.1 -C.sub.6) alkyl phenyl, or (C.sub.3 -C.sub.7) cycloalkyl, where said alkyl and phenyl R.sup.1 groups are optionally substituted with up to 3 methyl, ethyl, trifluoromethyl, or halo. Said preferred class of selective PDE4 inhibitors may be further illustrated by more preferred specific compounds of Formulas (4.0.1) and (4.0.2): ##STR7## PA1 wherein: the substituent moieties R.sup.6 and R.sup.7 both have the meanings set out in detail further below; in the presence of a base having a pK.sub.a numerical value in the range of from about 17 to about 30, provided that the difference in pK.sub.a numerical values between said base and the corresponding secondary nitrile of Formula (3.0.0) is no more than about 6; in an aprotic solvent having a dielectric constant (.di-elect cons.) of less than about 20; and at a temperature in the range of from about 0.degree. C. to about 120.degree. C.; whereby there is formed a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0) ##STR16## PA1 wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 ; and W.sup.1, W.sup.2, W.sup.3, W.sup.4 and W.sup.5 all have the same meanings as set out elsewhere herein. PA1 wherein: PA1 (I) each of the dashed lines is independently absent or a bond, so that single or double bonds result at the respective positions of an aromatic compound of Formula (1.0.0) or (2.0.0), provided that at least one of said dashed lines is a bond; PA1 (II) W.sup.1, W.sup.2, W.sup.3, W.sup.4, and W.sup.6 is each independently a member selected from the group consisting of: PA1 (III) R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is each independently selected so that: PA1 R.sup.6 and R.sup.7 are each independently selected from the group consisting of --N(R.sup.12).sub.2 ; (C.sub.1 -C.sub.6) alkyl substituted with 0-3 R.sup.9 ; --N(R.sup.12).sub.2 ; --SR.sup.12 ; --OR.sup.12 ; (C.sub.2 -C.sub.6) alkenyl substituted with 0-3 R.sup.9 ; (C.sub.3 -C.sub.6) alkynyl substituted with 0-3 R.sup.9 ; a (C.sub.3 -C.sub.14) carbocyclic ring system substituted with 0-3 R.sup.9 or 0-3 R.sup.10 ; and a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.10 ; or PA1 R.sup.6 and R.sup.7 are taken together to form a (C.sub.3 -C.sub.14) carbocyclic ring system substituted with 0-3 R.sup.9 or 0-3 R.sup.10 ; phenyl; 1- or 2-naphthyl substituted with 0-3 R.sup.9 or 0-3 R.sup.10 ; or a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl, and thiazolyl, said heterocyclic ring system being substituted with 0-2 R.sup.10 ; where: PA1 R.sup.9, R.sup.10, R.sup.12, R.sup.15 and R.sup.16 each have the same meaning as set out further above under the definitions of R.sup.1-5. PA1 wherein R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, and R.sup.25 are each independently selected from the group consisting of (C.sub.1 -C.sub.5) alkyl and phenyl; and X.sup.+ is a suitable cation, preferably selected from the group consisting of potassium, sodium, and lithium. A preferred base is one where each of R.sup.20 through R.sup.25 is methyl, resulting in KHMDS of Formula (5.0.0) above. Another preferred base is that where one R group on each Si atom is tert-butyl while the remaining R groups all have the meaning of methyl, e.g., R.sup.21 and R.sup.24 are both tert-butyl and R.sup.20, R.sup.22, R.sup.23, and R.sup.25 are each methyl. Yet another preferred base is that where two R groups on each Si atom is tert-butyl while the two remaining R groups both have the meaning of phenyl, e.g., and R.sup.20, R.sup.22, R.sup.23, and R.sup.25 are each tert-butyl and R.sup.21 and R.sup.24 are both phenyl.
The process of the present invention is one which is both facile and which affords acceptable yields of final product. The process of the present invention is distinguished from those heretofore available by the broad scope of its applicability, and by the criticality which has been discovered relating to the chemical makeup and reaction conditions of the base used to promote the reaction, as well as of the tertiary structure of the nitrile in the final product, both of which are described in detail further below.
The character of the base which is used in carrying out the process of the present invention is critical to obtaining the acceptable yields of tertiary-nitrile-substituted aromatic compound final product which serves to distinguish the process of the present invention from the processes of the prior art. The conjugate acid of the base which is used must have a pK.sub.a in the range of from about 17 to about 30. An example of a base which meets these critical requirements is the potassium, sodium or lithium salt of bis(trimethylsilyl)amide (KHMDS).
It has also been discovered in accordance with the present invention that the type of solvent which is used to carry out the reaction between a secondary nitrile and a substituted aromatic compound represents a choice which is critical to obtaining acceptable yields of final product. The solvent selected should be aprotic and have a dielectric constant (.di-elect cons.) of less than about 20. Toluene and tetrahydrofuran (THF) are examples of suitable solvents for use in the process of the present invention. The dielectric constant of THF is 7.6 and the dielectric constant of toluene is 2.4 (Handbook of Chemistry and Physics).
It will be appreciated that the nitrile reactant in the method of preparation of the present invention is "secondary", referring to the degree of substitution of the carbon atom to which the nitrile moiety is attached. In the final products prepared by the method of the present invention, it will be further understood that the carbon atom to which the nitrile moiety is attached is "tertiary", since it is not attached to any hydrogen atom.
The choice of the temperature at which the reaction mixture containing the secondary nitrile and aromatic compound is to be maintained is of less critical importance than the choice of the above-mentioned base or solvent. However, the proper reaction temperature is essential to obtaining acceptable yields of final product in accordance with the present invention, and should fall within the range of from about 0.degree. C. to about 120.degree. C.
The tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are characterized by a wide range of chemical structures and by a significant number of different practical utilities, which include both therapeutic and non-therapeutic applications of the said final products.
Preferred tertiary-nitrile-substituted aromatic compound final products prepared in accordance with the process of the present invention are those which are useful as therapeutic agents, especially inhibitors of phosphodiesterase type IV (PDE4). PDE4 inhibitors have applicability in therapeutic methods of treatment in humans and animals of many diseases, illnesses and conditions which are allergic or inflammatory in origin, especially including asthma, chronic obstructive pulmonary disease, bronchitis, rheumatoid arthritis and osteoarthritis, dermatitis, psoriasis, and allergic rhinitis.
Among such PDE4 inhibitors comprising tertiary-nitrile-substituted aromatic compound final products is a preferred class of selective PDE4 inhibitors disclosed in U.S. application Ser. No. 09/406,220, filed Sep. 27, 1999, now U.S. Pat. No. 6,127,398, issued Oct. 3, 2000; which is a division of U.S. application Ser. No. 08/963,904, filed Apr. 1, 1997, which is a continuation-in-part of U.S. provisional application Ser. No. 60/016861, filed May 3, 1996, now abandoned; and disclosed in International Application Ser. No. PCT/IB97/00323 based on said provisional application, filed Apr. 1, 1997, designating the United States, and published as WO 97/42174 on Nov. 13, 1997.
The above-mentioned preferred class of selective PDE4 inhibitors may be illustrated by the following generic Formula (4.0.0): ##STR6##
A method for preparing the above-described class of selective PDE4 inhibitors is described in U.S. application Ser. No. 09/153,762, filed Sep. 15, 1998, now U.S. Pat. No. 6,005,118 issued Dec. 21, 1999; which is a continuation-in-part of U.S. provisional application Ser. No. 60/064211, filed Nov. 4, 1997 and now abandoned; and in the corresponding European application based on said continuation-in-part application, filed Nov. 2, 1998 and published as EP-A-0 915 089 on May 12, 1999. In particular, there is disclosed in the above-mentioned applications the following synthesis procedure for treating an indazole of Formula (2.1.0) with cyclohexane 1,4-dicarbonitrile of Formula (3.1.0) to yield a tertiary-nitrile-substituted aromatic compound final product of Formula (4.0.3): ##STR8##
The above-illustrated synthesis procedure is described as being carried out in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide (KHMDS), lithium diisopropylamide, or lithium 2,2,6,6-tetramethylpiperidine. The above-mentioned bases are described as being selective and as permitting desirably high levels of addition of cyclohexane-1,4-dicarbonitrile, Formula (2.0.1), to the R- and R.sup.1 -substituted indazole, Formula (2.0.0), by displacement of the fluorine atom on the latter, while retaining both carbonitrile functionalities in place. It is further taught that it is preferred to use potassium bis(trimethylsilyl)amide (KHMDS) as the base promotant, in a solvent such as tetrahydrofuran, toluene, or xylene(s), preferably toluene, at a temperature between about 25.degree. C. and about 125.degree. C., preferably about 100.degree. C., for a period of from 1 hour to 15 hours, preferably about 5 hours, in order to obtain acceptable yields of a tertiary-nitrile-substituted aromatic compound final product of Formula (1.0.0).